(Verbatim from the application): Ventricular hypertrophy is a physiological adaptation by which the heart compensates for an increased workload, which may ultimately lead to decompensation and heart failure. The results of studies on the regulation of cardiac function in left ventricular hypertrophy (LVH) are still controversial. Interpretation of these studies is confounded in part by species difference, the duration or severity of the stimulus, and potential differences between in vivo physiological studies and in vitro studies. There are limitations to both in vivo and in vitro studies. For example, the extent to which geometric factors and loading conditions in LVH affect myocyte contraction in the heart, is an important limitation in vivo. Accordingly, two unique features of the current proposal include 1) physiological studies will be conducted both in vivo and in vitro from the same animals, and 2) the use of the large mammalian model which permits assessment of transmural differences in the observed contractile dysfunction as LVH progresses, from moderate to severe to failure. Furthermore, using transgenic mouse models, we will determine whether over expressing a specific protein, e.g. SR Ca2+ ATPase (SERCA), restores impaired contractile function observed in MHC403+ mice (.which exhibit LVH), or improves the defective Ca2+ handling observed in mice with pressure-overload LVH. The first hypothesis is that in severe, compensated LVH induced by chronic pressure-overload, in vivo inotropic and isotropic responses to Ca2+ are impaired. The impaired responses to Ca2+- are due both to intrinsic myocyte contractile function and to alterations in hemodynamics and geometric factors. The second hypothesis is that the mechanism of the impaired contractile and relaxation function in response to inotropic stimulation is due to an alteration in excitation-contraction coupling. The third hypothesis is that abnormal relaxation in LVH may in part be due to alterations in SERCA. Thus, genetic models demonstrating impaired relaxation will improve function by the addition of over expressed SERCA to the myocytes. These combined approaches, i.e., in vivo and in vitro in a large mammalian canine model and in transgenic mouse models, will provide significant new information regarding underlying mechanisms of contractile and relaxation dysfunction in LVH.
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